It is well known that medicinal agents are employed in the treatment of persons suffering from diabetes, hyperglycemia, and obesity. The compounds of the present invention achieve their antidiabetic, antihyperglycemic, and antiobesity effects by acting as selective agonists at .beta..sub.3 adrenergic receptors. The stimulation of these receptors on white and brown adipocytes promotes both lipolysis (breakdown of fat) and energy expenditure. Selective stimulation of .beta..sub.3 adrenergic receptors is important for chronic treatment. Stimulation of other .beta.-receptors could cause side effects such as increased heart rate (.beta..sub.1 effect) and/or muscle tremor (.beta..sub.2 effect). The compounds of the present invention show high selectivity for .beta..sub.3 adrenergic receptors.
Bloom, et al., U.S. Pat. No. 5,061,727, disclose substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles of general formula (I) ##STR3## wherein R.sup.1 and R.sup.4 may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, C.sub.1 to C.sub.4 thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consisting of ##STR4## wherein R' is selected from the group consisting of hydrogen, C.sub.1 to C4 alkyl and C.sub.1 to C.sub.4 acyl and Y is selected from the group consisting of carbonyl and thiocarbonyl; R.sup.2 and R.sup.3 may be the same or different and are selected from the group consisting of hydrogen and C.sub.1 to C.sub.4 alkyl; R.sup.5 and R.sup.6 are selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, --CH.sub.2 OCH.sub.2 COOR.sub.7 and --CH.sub.2 OCH.sub.2 CH.sub.2 OR.sub.7, where R.sup.7 is hydrogen or C.sub.1 to C.sub.4 alkyl; with the provision that R.sup.5 and R.sup.6 may not both be hydrogen; which have antihyperglycemic and antiobesity activity.
The synthesis, antidiabetic effects, and antiobesity effects of (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodiox ole-2,2-dicarboxylate, disclosed by Bloom, et al. in U.S. Pat. No. 5,061,727, are detailed in Bloom, et al. J. Med. Chem., 1992, 35, 3081, Largis, et al. Drug Dev. Res., 1994, 32, 69, and Bloom, et al. Drugs of the Future, 1994, 19, 23.
The compounds of the present invention contain a 1,4-benzodioxine ring, whereas the compounds in Bloom, et al., U.S. Pat. No. 5,061,727 contain a 1,3-benzodioxole. They retain high selectivity for the .beta..sub.3 receptor and show much higher antiobesity and antihyperglycemic activity in animal models. Therefore, the compounds of this invention are useful in treating diabetes, hyperglycemia, and obesity, exhibiting minimal side effects such as heart rate increase and/or muscle tremor in humans and animals, when formulated into pharmaceutical compositions. Health-conscious individuals today are making an effort to reduce body fat through exercise and low fat diet. An invention compound can help a human reduce body fat and through treatment of domestic edible animals such as cattle, swine, sheep, goats, turkeys and chickens can provide leaner meats for human consumption.